Lung immaturity is a major cause of morbidity in premature infants and lung diseases affect millions every year. This grant addresses how lung development is controlled by the Nuclear Factor I B transcription factor (NFIB) and other NFI family members. We have shown that disruption of Nfib causes perinatal lethality in mice due to a failure in lung maturation. We hypothesize that Nfib expression in lung mesenchyme is essential for lung maturation. To test this hypothesis we will: 1) Identify target genes of Nfib needed for mouse lung maturation. Nfib knockout (KO) mice die at birth due to lung immaturity. We will find the target genes of Nfib in lung maturation, assess changes in growth properties of cells from Nfib-/- lungs and determine whether the block in maturation can be overcome by glucocorticoids, a standard treatment for human fetal lung immaturity. 2) Generate a conditional knockout allele of Nfib and eliminate Nfib function separately in different cell populations in the lung, to determine in which cells Nfib is needed for lung maturation. This will directly test of hypothesis that Nfib is essential in lung mesenchyme. 3) Determine how other NFI family members cooperate with or antagonize Nfib function in lung development by making mice deleted for 2 NFI genes simultaneously, Nfib+Nfic and Nfib+Nfix. We propose that these NFI genes interact with Nfib in lung development and in the development of other organs. These studies will yield new insights into the molecular mechanisms of lung development and how they are regulated by the highly-conserved NFI transcription factor family.